ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.
ATR promotes clearance of damaged DNA and damaged cells by rupturing micronuclei.
复制标题
DOI：
10.1016/j.molcel.2023.09.003
复制
发表时间：
2023-09
期刊：
影响因子：
16
通讯作者：
Yoon Ki Joo;Elizabeth M. Black;Isabelle Trier;W. Haakma;Lee Zou;Lilian Kabeche
中科院分区：
文献类型：
--
作者：
Yoon Ki Joo;Elizabeth M. Black;Isabelle Trier;W. Haakma;Lee Zou;Lilian Kabeche
人共济失调毛细血管扩张症突变和Rad 3相关（ATR）激酶在细胞核中发挥功能以保护基因组完整性。微核（MN）是由基因组和染色体的不稳定性引起的，可引起非整倍体和染色体断裂，但MN是如何被去除的还不清楚。在这里，我们表明ATR在MN中是活跃的，并通过在Ser 395处磷酸化核纤层蛋白A/C促进其在S期破裂，这引发Ser 392的CDK 1磷酸化并使MN包膜不稳定。在携带MN的细胞中，ATR或CDK 1抑制减少MN破裂。因此，ATR抑制剂（ATRi）减少了细胞质DNA传感器cGAS的激活，并损害了MN中cGAS依赖性自噬体的积累和微核DNA的清除。此外，ATRi减少cGAS介导的衰老和自然杀伤细胞对携带MN的癌细胞的杀伤。因此，除了典型的ATR信号传导途径之外，ATR-CDK 1-核纤层蛋白A/C轴促进MN断裂以清除受损的DNA和细胞，通过意想不到的细胞自主和细胞非自主机制保护细胞群体中的基因组。
The human ataxia telangiectasia mutated and Rad3-related (ATR) kinase functions in the nucleus to protect genomic integrity. Micronuclei (MN) arise from genomic and chromosomal instability and cause aneuploidy and chromothripsis, but how MN are removed is poorly understood. Here, we show that ATR is active in MN and promotes their rupture in S phase by phosphorylating Lamin A/C at Ser395, which primes Ser392 for CDK1 phosphorylation and destabilizes the MN envelope. In cells harboring MN, ATR or CDK1 inhibition reduces MN rupture. Consequently, ATR inhibitor (ATRi) diminishes activation of the cytoplasmic DNA sensor cGAS and compromises cGAS-dependent autophagosome accumulation in MN and clearance of micronuclear DNA. Furthermore, ATRi reduces cGAS-mediated senescence and killing of MN-bearing cancer cells by natural killer cells. Thus, in addition to the canonical ATR signaling pathway, an ATR-CDK1-Lamin A/C axis promotes MN rupture to clear damaged DNA and cells, protecting the genome in cell populations through unexpected cell-autonomous and cell-non-autonomous mechanisms.